Haematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFβ availability

Nat Commun. 2016 Jan 8:7:10222. doi: 10.1038/ncomms10222.

Abstract

The life-long maintenance of haematopoietic stem and progenitor cells (HSPCs) critically relies on environmental signals produced by cells that constitute the haematopoietic niche. Here we report a cell-intrinsic mechanism whereby haematopoietic cells limit proliferation within the bone marrow, and show that this pathway is repressed by E-selectin ligand 1 (ESL-1). Mice deficient in ESL-1 display aberrant HSPC quiescence, expansion of the immature pool and reduction in niche size. Remarkably, the traits were transplantable and dominant when mutant and wild-type precursors coexisted in the same environment, but were independent of E-selectin, the vascular receptor for ESL-1. Instead, quiescence is generated by unrestrained production of the cytokine TGFβ by mutant HSPC, and in vivo or in vitro blockade of the cytokine completely restores the homeostatic properties of the haematopoietic niche. These findings reveal that haematopoietic cells, including the more primitive compartment, can actively shape their own environment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Marrow / metabolism*
  • Cell Proliferation*
  • Chemokines / metabolism*
  • Cytokines / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Hematopoietic Stem Cells / metabolism*
  • Homeostasis
  • In Vitro Techniques
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Receptors, Fibroblast Growth Factor / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sialoglycoproteins / genetics*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Chemokines
  • Cytokines
  • Receptors, Fibroblast Growth Factor
  • Sialoglycoproteins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • cysteine-rich fibroblast growth factor receptor